Scientists slow development of Alzheimer’s trademark cell-killing plaques

University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer’s patients and appears to be a major cause of the disease.

They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer’s patients—plaques that kills cells and contributes to memory loss and other Alzheimer’s symptoms.

The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to ‘rescue’ the Golgi structure.

"We plan to use this as a strategy to delay the disease development," said Yanzhuang Wang, U-M associate professor of molecular, cellular and developmental biology. "We have a better understanding of why plaque forms fast in Alzheimer’s and found a way to slow down plaque formation."

The paper appears in an upcoming edition of the Proceedings of the National Academy of Sciences. Gunjan Joshi, a research fellow in Wang’s lab, is the lead author.

Wang said scientists have long recognized that the Golgi becomes fragmented in the neurons of Alzheimer’s patients, but until now they didn’t know how or why this fragmentation occurred.

The Golgi structure has the important role of sending molecules to the right places in order to make functional cells, Wang said. The Golgi is analogous to a post office of the cell, and when the Golgi becomes fragmented, it’s like a post office gone haywire, sending packages to the wrong places or not sending them at all.

U-M researchers found that the accumulation of the Abeta peptide—the primary culprit in forming plaques that kill cells in Alzheimer’s brains—triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65.

Wang and colleagues rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent.

The next step is to see if Golgi fragmentation can be delayed or reversed in mice, Wang said. This involves a collaboration with the Michigan Alzheimer’s Disease Center at the U-M Health System, directed by Dr. Henry Paulson, professor of neurology, and Geoffrey Murphy, assistant professor of physiology and research professor at the U-M Molecular and Behavioral Neuroscience Institute.

Hypertension Could Bring Increased Risk for Alzheimer’s disease

A study in the Journal of the American Medical Association Neurology suggests that controlling or preventing risk factors, such as hypertension, earlier in life may limit or delay the brain changes associated with Alzheimer’s disease and other age-related neurological deterioration.

Dr. Karen Rodrigue, assistant professor in the UT Dallas Center for Vital Longevity (CVL), was lead author of a study that looked at whether people with both hypertension and a common gene had more buildup of a brain plaque called amyloid protein, which is associated with Alzheimer’s disease. Scientists believe amyloid is the first symptom of Alzheimer’s disease and shows up a decade or more before symptoms of memory impairment and other cognitive difficulties begin. The gene, known as APOE 4, is carried by 20 percent of the population.

Until recently, amyloid plaque could be seen only at autopsy, but new brain scanning techniques allow scientists to see plaque in living brains of healthy adults. Findings from both autopsy and amyloid brain scans show that at least 20 percent of typical older adults carry elevated levels of amyloid, a substance made up mostly of protein that is deposited in organs and tissues.

“I became interested in whether hypertension was related to increased risk of amyloid plaques in the brains of otherwise healthy people,” Rodrigue said. “Identifying the most significant risk factors for amyloid deposition in seemingly healthy adults will be critical in advancing medical efforts aimed at prevention and early detection.”

Based on evidence that hypertension was associated with Alzheimer’s disease, Rodrigue suspected that the combination of hypertension and the presence of the APOE-e4 gene might lead to particularly high levels of amyloid plaque in healthy adults.

Genome-wide imaging study identifies new gene associated with Alzheimer’s plaques

A study combining genetic data with brain imaging, designed to identify genes associated with the amyloid plaque deposits found in Alzheimer’s disease patients, has not only identified the APOE gene — long associated with development of Alzheimer’s — but has uncovered an association with a second gene, called BCHE.

A national research team, led by scientists at the Indiana University School of Medicine, reported the results of the study in an article in Molecular Psychiatry posted online Tuesday. The study is believed to be the first genome-wide association study of plaque deposits using a specialized PET scan tracer that binds to amyloid.

The research also is believed to be the first to implicate variations in the BCHE gene in plaque deposits visualized in living individuals who have been diagnosed with Alzheimer’s disease or are at-risk for developing the disease. The enzyme coded by the BCHE gene has previously been studied in post-mortem brain tissue and is known to be found in plaques.

“The findings could recharge research efforts studying the molecular pathways contributing to amyloid deposits in the brain as Alzheimer’s disease develops and affects learning and memory,” said Vijay K. Ramanan, the paper’s first author and an M.D./Ph.D. student at the IU School of Medicine.

The BCHE gene finding “brings together two of the major hypotheses about the development of Alzheimer’s disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences at IU and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.

Scientists have long pointed to the loss of an important brain neurotransmitter, acetylcholine, which is depleted early in the development of the disease, as a key aspect of the loss of memory related neurons. The BCHE gene is responsible for an enzyme that breaks down acetylcholine in the brain. The other major Alzheimer’s hypothesis holds that the development of the amyloid plaques is the primary cause of the disease’s debilitating symptoms. As it turns out, the enzyme for which the BCHE gene codes is also found in significant quantities in those plaques.

“This study is connecting two of the biggest Alzheimer’s dots,” said Dr. Saykin, director of the Indiana Alzheimer Disease Center and the IU Center for Neuroimaging at the IU Health Neuroscience Center.

“The finding that BCHE gene variant predicts the extent of plaque deposit in PET scans among people at risk for Alzheimer’s disease is likely to reinvigorate research into drugs that could modify the disease by affecting the BCHE enzyme or its metabolic pathway,” he said. Some existing drugs inhibit this enzyme, but it is unclear whether this influences plaque deposits.

Overall, the results appear to offer scientists new potential targets for drugs to slow, reverse or even prevent the disease. Alzheimer’s disease affects an estimated 5.4 million Americans and has proven resistant to treatments that do more than temporarily slow the worsening of symptoms.

Amyloid plaque deposits build up abnormally in the brains of Alzheimer’s patients and are believed to play an important role in the memory loss and other problems that plague patients.

The study makes use of an imaging agent, florbetapir, now approved for use by the U.S. Food and Drug Administration, that allows physicians to see the level of plaque buildup in a patient’s brain, something that previously could be determined only with an autopsy.

In a genome-wide association study, researchers evaluate alternate versions of many genes to determine whether particular genetic variants are associated with a particular trait — in this case, the amounts of amyloid plaque deposits that the PET scans revealed in the brains of study participants.

Using the imaging agent that enables detection of the plaques in the brain, the researchers conducted PET scans of 555 participants in the Alzheimer’s Disease Neuroimaging Initiative, a long-term public-private research project that includes people at risk for Alzheimer’s disease and patients who have been diagnosed with the disease as well as participants with no symptoms.

With sophisticated statistical analyses, the imaging data was combined with analyses of DNA collected from the 555 participants to determine whether particular gene variants were found more often among patients with higher levels of plaque deposits.

The analysis found that a variant in BCHE was significantly associated with the levels of plaque deposits. As would be expected, the analysis also found a strong association with variants of another gene, APOE, that has long been known to be associated with the development of Alzheimer’s. The effect of BCHE was independent of APOE, however. Moreover, the effects of the two genes were additive — that is, people with the suspect variants of both genes had more plaque deposits than people who had only one of the variants associated with plaque development.

It’s Not Just Amyloid: White Matter Hyperintensities and Alzheimer’s Disease

New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.

Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualized as white matter hyperintensities (WMHs).

The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuroimaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mildcognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.

Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits.

“White Matter Hyperintensities and Cerebral Amyloidosis” was published online in JAMA Neurology.